Citation and License

Arthritis Research & Therapy 2012, 14:226
doi:10.1186/ar4071

Published: 31 October 2012

Abstract

Recent genome-wide association studies have implicated the tumor necrosis factor receptor-associated
factor 3-interacting protein 2 (TRAF3IP2) gene and its product, nuclear factor-kappa-B
activator 1 (Act1), in the development of psoriatic arthritis (PsA). The high level
of sequence homology of the TRAF3IP2 (Act1) gene across the animal kingdom and the
presence of the Act1 protein in multiple cell types strongly suggest that the protein
is of importance in normal cellular function. Act1 is an adaptor protein for the interleukin-17
(IL-17) receptor, and recent observations have highlighted the significance of IL-17
signaling and localized inflammation in autoimmune diseases. This review summarizes
data from recent genome-wide association studies as well as immunological and molecular
investigations of Act1. Together, these studies provide new insight into the role
of IL-17 signaling in PsA. It is well established that IL-17 activation of tumor necrosis
factor receptor-associated factor 6 (TRAF6) signaling pathways normally leads to nuclear
factor-kappa-B-mediated inflammation. However, the dominant PsA-associated TRAF3IP2
(Act1) gene single-nucleotide polymorphism (rs33980500) results in decreased binding
of Act1 to TRAF6. This key mutation in Act1 could lead to a greater association of
the IL-17 receptor with TRAF2/TRAF5 and this in turn suggests an alternative function
for IL-17 in PsA. The recent observations described and discussed in this review raise
the clinically significant possibility of redefining the immunological role of IL-17
in PsA and provide a basis for defining future studies to elucidate the molecular
and cellular functions of Act1.